The relationship of 5,5-diphenylhydantoin metabolism to the species-specific induction of gingival hyperplasia in the rat

Abstract

Chronic administration of 5,5-diphenylhydantoin (DPH) is known to produce gingival hyperplasia in man but not in most other species. To evaluate the importance of rate of DPH metabolism on this effect, the plasma half-life of DPH was determined in rats. Drug half-life was found to be significantly shorter (0·5-2 hr) than reported by other investigators for man (4–29 hr). Since this short DPH plasma half-life in the rat may be related to failure of the drug to induce gingival hyperplasia, further studies utilized SKF 525A to inhibit drug metabolism. This compound increased DPH plasma half-life 7-fold, and lowered plasma free 5-( p-hydroxyphenyl)5-phenylhydantoin (HPPH) levels. These data show that SKF 525A inhibits DPH metabolism. Elevated plasma DPH levels were attained by concurrent administration of SKF 525A and DPH during chronic administration studies. These chronic studies in which DPH levels comparable to human therapeutic levels were attained, failed to produce gross or histological signs of gingival inflammation or of gingival hyperplasia. These results suggest that factors other than high plasma drug levels alone may be required to explain the species-response difference observed in the drug-induced pathology.